S-alkylcysteines are known compounds, widely described in the literature.
For example, S-methylcysteines are claimed in WO 97/14430 (Pharmacia & Upjohn) as antioxidants for peptides and proteins, or they are used in the treatment of hepatic pathologies [Chemical Abstracts 106:169054p (1987)] or they are also used as oral antiseborrheic agents in U.S. Pat. No. 3,950,542 (Oreal S. A.).
Brown et al. describe S-ethylcysteines as antitubercolar agents [J. Am. Chem. Soc., 76, 3860 (1954)].
Moreover, S-alkylcysteines can be used as synthetic intermediates for the preparation of compounds with pharmacological activity.
In particular, S-methylcysteines are used, for example, in the synthesis of antihypertensive agents (EP 266950--Pfizer; EP 254032--Schering), of antiviral agents (U.S. Pat. No. 5,644,028--Japan Energy Corporation), of antithrombotic agents (WO 95/28420--Corvas International, Inc.) or of metalloprotease inhibitors (WO 96/11209--Chiroscience Limited).
Several processes for the preparation of S-alkylcysteines are described in the literature.
In these context, the alkylation processes of the mercapto group of cysteines are of particular interest.
For example, D. H. Hwang et al. [J. Org. Chem., 50, 1264 (1985)] describe the preparation of S-methyl-L-cysteine by methylating L-cysteine hydrochloride with methyl iodide and sodium ethoxide, the latter being formed in situ from metallic sodium and ethanol, in alcoholic medium.
M. Frankel et al. [J. Chem. Soc., 1390 (1960)] report a process for the S-methylation of L-cysteine by Schotten-Baumann reaction in hydroalcoholic medium and in the presence of sodium hydroxide as a base and of methyl iodide as methylating agent.
According to a further version, described by H. Zahan et al. (Chemical Abstracts 49 6834e) the methylation reaction is carried out with methyl iodide and sodium bicarbonate in ethanol.
However, the use of methyl iodide shows not to be the best for the application on a large scale, because of its high toxicity and cost and because of the formation of elementary iodine which is difficult to dispose in the waste waters deriving from the work-up.
According to a similar synthetic process described by M. D. Amstrong et al. [J. Org Chem., 16, 749 (1951)], S-ethyl-L-cysteine is prepared by S-ethylating with ethyl bromide the L-cysteine obtained in situ from L-cystine by reduction with metallic sodium and liquid ammonia. It is evident that, from an industrial viewpoint, this process results to be still more disadvantageous with respect to the previous ones because, in addition to the use of a toxic alkylating agent, it requires particular procedures and equipment for the storage and use of liquid ammonia under safety conditions.
Further processes described in the literature use different methylating agents.
For example, the use of dimethylsulfate in the presence of barium hydroxide is described by V. du Vigneaud et al. [J. Biol. Chem., 105, 481 (1934)], but also dimethylsulfate is characterised by a high toxicity. The use of trimethylphosphate in aqueous solution at pH=8 is described by K. Yamauchi [Tet. Lett., 1199 (1977)], but this alkylating agent is toxic by inhalation, skin contact or ingestion. Furthermore this synthesis results in a partial racemization (7.5%) of the substrate.
Most of the processes described in the literature for the synthesis of S-alkylcysteines uses an amount of alkylating agent higher than the stoichiometric one to bring to completion the alkylation reaction within an acceptable time period without using too much strong reaction conditions.
A drawback common to the above processes is the formation of significant amounts of salts, for example iodides or sulfates, deriving from the reaction itself but also from the decomposition process of the exceeding alkylating agent, during the final work-up.
Consequently, the isolation of very soluble S-alkylcsysteines, such as S-methylcysteine, from an aqueous medium is particularly cumbersome so resulting in some cases in unsatisfactory yields.
Less common methylating agents, which can be used for the preparation of S-methylcysteines by S-methylation of cysteines, are the sulphonium salts of formula RMe.sub.2 SI, described by K. Yamauchi [J. Chem. Soc. Perkin Trans. I, 1941 (1983)]. However such alkylating agents, which can be easy removed by simple thermal decomposition and extraction with chlorinated solvents, are of no practical interest because they are not commercially available.
Therefore, the high toxicity or harmfulness of the alkylating agents, their high costs, the inevitable formation of remarkable amounts of salts in the reaction medium, so making complicate the process for the isolation of the final water-soluble product, and of waste waters difficult to dispose, the partial racemization of the substrate and, finally, the poor commercial availability of some reagents make the processes for the preparation of S-alkylcysteines described in the literature of difficult industrial applicability.
As far as we know, a process for the preparation of S-alkylcysteines by S-alkylation reaction with dialkylcarbonates has never been described in the literature.